Previous morphometric studies reveal an age-related increase in the average dendritic extent of neurons in some regions that show an age- related loss of neurons, suggesting a plastic, compensatory response of surviving neurons to the death of their neighbors. This response is not observed in Alzheimer's disease (AD). Other observations reveal proliferation and activation of glial cells in AD and normal aging as well as in response to neuronal injury and death. It is hypothesized that dying neurons signal glial cells to proliferate and become activated, and that these activated glial cells in turn produce neuronotrophic and neurite elongation factors which influence the surviving neurons. We further hypothesize that this signaling system is not intact in AD. Interleukin-1Beta (IL-1BETA) has been recognized as a key activator of astrocyte growth and protein expression and appears to play a major role in the response of glia to neuronal death. Furthermore, IL-1Beta has been shown to be elevated in AD brain. In order to better understand the role of IL-1Beta in the normal glial response to neuron loss as well as provide tools for testing the possibility that these responses are aberrant in AD, we have used high-resolution giant two-dimensional (2-D) gel electrophoresis to characterize secreted proteins that are induced in rat astrocyte treated with il-1Beta. Our initial investigations have revealed eight protein species that are secreted in response to IL-1Beta; to our knowledge, seven of these proteins have not been previously described. In this proposal we plan to: 1) Identify, characterize, and microsequence partially purified IL-1Beta responsive proteins from high resolution giant 2-D gels 2) Construct degenerate sets of oligonucleotides from microsequence to clone cDNAs 3) Determine mRNA levels for the human homologues of these proteins in affected regions from AD and control brains (this may require cloning of human homologues). These investigations will provide important information about the proposed signaling cascade between dying neurons and their neighbors and thus have relevance to our understanding of the normal glial/glial and glial/neuronal interactions occurring in normal development, aging, neuronal injury, and neurodegenerative disorders. Furthermore, these studies directly examine a part of the signaling cascade which may be deficient in Alzheimer's disease.